Optically active 2-amino-1-phenylethanol derivatives of formula (I) have been used in the preparations of several agricultural chemicals, medical supplies, fine chemicals and building blocks, and 60 biologically active substances having 2-amino-1-phenylethanol moiety have been identified to date.

Representative examples of drugs containing 2-amino-1-phenylethanol derivatives include blockbuster drugs such as Paroxetine (Paxil, anti-depression agent) and Salmeterol (Seretide, anti-asthma agent) (Chemistry Today (2006), 24, 40); currently available drugs such as Fluoxetin (Prozac), Sotalol (Betapace), Formotero (Foradil) and Fexofenadine (Allegra), which are derived from chiral switches in the pipeline (Nature Rev. Drug Discov. (2002), 1, 753-768); adrenoceptor agonists such as Tulobuterol, Metaproterenol, Fenoterol and Terbutaline; and NR1/2B subtype NMDA receptor antagonists such as Ifenprofil and Eliprodil. Further, there are several candidate drugs having 2-amino-1-phenylethanol moiety under development, which include adrenoceptor agonists such as Albuterol, Calcimimetics, Terbutaline, Ritodrine, Salmeterol, Suloctidil and Synephrine; NR1/2B subtype NMDA receptor antagonists such as CP-101,606 and Ro-25-6981 (Bioorg. Med. Chem. Lett. (2002), 12, 2615-2619); antidiabetics (U.S. Pat. No. 5,817,689); anti-obesity agents (U.S. Pat. No. 5,817,689 and J. Med. Chem. (1999), 42, 181-201); and anti-depressants (U.S. Pat. No. 4,707,497 and Tetrahedron (2001), 57, 1849-1855).
Generally, the compound of formula (I) is prepared by a conventional method using essential intermediates of formulae (II) to (IV).

wherein, X is a halogen atom such as —Cl and —Br, or a leaving group such as mesyloxy (—OMs) and tosyloxy (—OTs); Y is —NH2, primary or secondary amine, —N3, or —CN; and R is hydrogen, halogen, alkyl, hydroxy, amine, —NO2 or —CF3 substituted in the ortho-, metha- or para-position of the phenyl group.
Accordingly, there have been numerous attempts to develop the preparations of optically active intermediates of formulae (II) to (IV). For example, a number of studies disclosed the methods for preparing the compound of formula (II) or (IV), comprising asymmetric reduction of α-substituted acetophenones using oxazaborolidine catalyst and borane (Angew. Chem. Int. Ed. (1998), 37, 1986-2012; Tetrahedron Lett. (1997), 38, 1125-1128; and Tetrahedron Lett. (2001), 42, 8919-8921), asymmetric reduction of α-substituted acetophenones using asymmetric transfer hydrogenation (Org. Lett. (2005), 7, 5489-5491; Org. Lett. (2002), 4, 4373-4376; and Japanese Patent Publication No. 2002-251994); asymmetric reduction of aminoketone using hydrogen at high pressure (J. Am. Chem. Soc. (2000), 122, 6510-6511); synthesis of diol using asymmetric dihydroxylation (Tetraderon: Asymmetry (2004), 15, 3955-3959); asymmetric acylation of α-azidoalcohol using enzymes (Tetraderon: Asymmetry (2004), 15, 3939-3944); or reduction of α-azidoketone using microorganisms (Tetraderon: Asymmetry (2001), 12, 3381-3385; and J. Mol. Cat. B: Enzymatic (2006), 39, 9-12).
Among these methods, the asymmetric reduction of α-substituted acetophenones using oxazaborolidine catalyst and borane is mainly employed in the preparation of the compound of formulae (II) to (IV); however, such method require high cost due to the use of an expensive catalyst in an excess amount, and have the wide fluctuation of the optical activity of the product depending on the substitution of the phenyl moiety, in addition, the reduction is highly sensitive to humidity.
Further, the asymmetric reduction of aminoketone using hydrogen at high pressure can be conducted only when the amino group of aminoketone is disubstituted, it is difficult to derivatize the product thereof, and the hydrogen gas used in the reduction is danger.
Although the asymmetric reduction of α-substituted acetophenones using asymmetric transfer hydrogenation is an effective method for the preparation of the intermediates, α-substituent of acetophenones such as —Cl, —N3 or —CN is known to be harmful to the skin and eyes. Furthermore, it is difficult to apply the method on the mass production due to its poor light stability, and low e.e. (enantiomer excess) value of the product thereof, e.g., α-azido- or α-cyano-acetophenone.